EP0585026B1 - Use of fatty acids for increasing gut calcium absorption - Google Patents
Use of fatty acids for increasing gut calcium absorption Download PDFInfo
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- EP0585026B1 EP0585026B1 EP93306444A EP93306444A EP0585026B1 EP 0585026 B1 EP0585026 B1 EP 0585026B1 EP 93306444 A EP93306444 A EP 93306444A EP 93306444 A EP93306444 A EP 93306444A EP 0585026 B1 EP0585026 B1 EP 0585026B1
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- Prior art keywords
- gla
- acid
- calcium
- dgla
- administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- This invention relates to fatty acid treatments, and in particular to enhancing absorption of calcium from the gut,
- the acids which in nature are of the all-cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. delta-9,12-octadecadienoic acid or delta-4,7,10,13,16,19 docosahexaenoic acid, but numerical designations such as, correspondingly, 18:2 n-6 or 22:6 n-3 are convenient.
- n-3 series only 18:3 n-3 has a commonly used trivial name, alpha-linolenic acid, though the name stearidonic acid is coming into use for the 18:4 n-3 acid and the names eicosapentaenoic acid and docosahexanenoic acid as such are also used.
- the alpha isomer of linolenic acid was characterised earlier than gamma-linolenic acid and reference in the literature simply to linolenic acid, especially in the earlier literature, is to the alpha-acid.
- Laval-Jeantet et al disclose the stimulating effect of linoleic and alpha-linolenic acids on calcium absorption (Pathologie Biologie, vol. 24(3), 1976, pages 213-225).
- EP-0261814 discloses that the conversion of gammalinolenic acid to dihomogammalinolenic acid is inhibited by low calcium levels.
- the document teaches the co-administration of both calcium and these fatty acids to ensure that lack of either is not a limiting factor and proposes that this treatment may be of benefit in bone disorders involving calcium loss from the bones.
- GLA gamma-linolenic acid
- EPA eicosapentaenoic acid
- GLA is the first metabolite of linoleic acid, the major essential fatty acid in the diet. Linoleic acid is converted to GLA by the enzyme delta-6-desaturase. However, this step is slow and rate limiting even in the normal body and as a result there are advantages in the administration of GLA directly.
- the invention in one aspect lies in the use of GLA and/or its immediate and rapidly produced metabolite dihomogammalinolenic acid (DGLA), in the preparation of a medicament for, or in a method of, securing increase of gut calcium absorption.
- DGLA immediate and rapidly produced metabolite dihomogammalinolenic acid
- LA linoleic acid
- the invention therefore includes the use of linoleic acid, and as noted below has particular reference to calcium deficiency disease.
- the invention may be regarded as lying in a method of increasing the systemic calcium pool by stimulating both an increased absorption of and a reduction of urinary excretion of calcium, wherein an effective daily amount of GLA or DGLA, or LA, is administered in any convenient form to animals or humans particularly those suffering from or at risk of calcium deficiency disease.
- the invention further includes the use of GLA, DGLA or LA in the preparation of a medicament for such a method.
- the invention may be regarded simply as the treatment or prevention condition defining disease in either animals or humans.
- GLA in the body is very rapidly converted to dihomo-gamma-linolenic acid (DGLA); DGLA therefore has a very similar effect to GLA.
- DGLA dihomo-gamma-linolenic acid
- GLA or DGLA may be used in any appropriate form, including but not limited to triglyceride, diglyceride, monoglyceride, free fatty acid, any appropriate ester, any appropriate salt including the lithium, sodium, potassium, calcium, zinc, magnesium or other salt, phospholipid, amide or any other pharmacologically acceptable form.
- the preferred dose range is 0.01 to 1,000 mg/kg/day, more preferably 0.5 to 50 mg/kg/day, very preferably 2 to 30 mg/kg/day of GLA or DGLA, and medicaments are readily prepared in dosage unit form to administer such amounts (related to a 70 kg human adult).
- the GLA or DGLA may be used with any essential fatty acids of the n-6 or n-3 series, including, for example, arachidonic acid, alpha-linolenic acid, eicosapentaenoic acid or docosahexaenoic acid, in like doses.
- GLA in combination with EPA and/or its metabolite DHA is desirable, producing particularly advantageous effects.
- parenteral sub-cutaneous, intramuscular, intravenous or by any other appropriate route
- enteral topical in the form of appropriate GLA-containing ointments, creams, lotions, patches, etc. vaginal or rectal are among suitable routes of administration.
- the acids may be used as such or as pharmaceutically acceptable and physiologically equivalent derivatives as, for example, detailed herein for GLA and DGLA, and reference to any of the acids is to be taken as including reference to the acids when in the form of such derivatives. Equivalence is demonstrated by entry into the pathway quoted herein, as evidenced by effects corresponding to those of the acids themselves or their natural glyceride esters.
- the method is suitably that plasma samples (1 ml) are extracted with chloroform:methanol (2:1). The extract is filtered through sodium sulphate, evaporated to dryness, and taken up in 0.5 ml chloroform:methanol. The lipid fractions are separated by thin layer chromatography or silica gel plates. The phospholipid fraction, taken to reflect essential fatty acid contents most sensitively, is methylated using boron trifluoride-methanol. The resulting methyl esters of the fatty acids are separated and measured using a Hewlett-Packard 5880 gas chromatograph with a six foot column packed with 10% Silar on Chromosorb WAW 106/230. The carrier gas is helium (30 ml/min).
- Oven temperature is programmed to rise from 164°C to 190°C at 2°C/min.
- Detector temperature is 220°C and injector temperature 200°C.
- Retention times and peak areas are automatically computed by Hewlett-Packard Level 4 integrator. Peaks are identified by comparison with standard fatty acid methyl esters.
- the invention is chiefly described in terms of methods of treatment and in the use of GLA or DGLA in the preparation of pharmaceutical compositions, but it will be understood that the gamma-linolenic and other EFAs, being in the nature of dietary supplements, can be incorporated in a dietary margarine or other foodstuff and such are to be understood as within the term pharmaceutical composition or medicament herein (including the claims) when for the purposes set out.
- compositions may be produced for use in the invention by associating the natural or synthetic acids, as such or as derivatives, with an acceptable pharmaceutical vehicle. It is, however, at present convenient to provide at least GLA in the form of an available oil having a high GLA content, hence reference to "oils" herein.
- oils are available in the seed of evening primrose species such as Oenothera biennis L. and Oenothera lamarckiana , the oil extract therefrom containing about 8% GLA and about 72% linoleic acid in the form of their glycerides, together with other glycerides (percentages based on total fatty acids).
- GLA is borage species such as Borago officinalis which provide a richer source than Oenothera oil.
- Oils from the seeds of members of the Ribes family are also often rich in GLA. Recent studies on fungi which can be cultivated by fermentation promise a fungal oil source. Some algae also produce GLA and may be harvested or cultured. Synthesis is also possible.
- the oil is extracted from the seed by one of the conventional methods of extraction such as cold pressure, screw pressure after partially cooking the seed, or solvent extraction.
- seed oil extracts referred to above can be used as such or can, for example, if desired, be fractionated to yield an oily composition containing the triglycerides of gamma-linolenic and linoleic acids as the main fatty acid components, the gamma-linolenic acid content being, if desired, a major proportion. Seed oil extracts appear to have a stabilising effect upon DGLA if present.
- DGLA can be prepared by chemical synthesis or by fungal or algal fermentation.
- natural sources of 22:4 and 22:5 n-6 acids include adrenal glands (22:5) and kidneys (22:4) obtained from slaughter houses, which also give arachidonic acid (AA) sources.
- n-3 acids have long been available from marine oils, particularly the 20:5 n-3 (EPA) and 22:6 n-3 (DHA) acids, and more recently from microbial and algal fermentation. They can be isolated from these sources by, for example, saponification under mild non-oxidising conditions followed by preparative gas liquid chromatography. Synthesis is difficult but not impossible and provides another source.
- EPA 20:5 n-3
- DHA 22:6 n-3
- compositions are conveniently in a form suitable for oral, topical, parenteral or other route of administration in a suitable pharmaceutical vehicle, well known generally for any particular kind of preparation.
- a suitable pharmaceutical vehicle well known generally for any particular kind of preparation.
- tablets, capsules, ingestible liquid or powder preparations can be prepared as required, and topical preparations also when the gamma-linolenic acid or other acids are absorbed through the skin.
- injectable solutions of hydrolysed Oenothera or other oil may be prepared using albumin to solubilise the free acid.
- Emulsions and salts can also be administered by infusion or injection.
- a preservative is incorporated into the preparation.
- Alpha-tocopherol in a concentration of about 0.1% by weight has been found suitable for the purpose and is one of a number of possible stabilisers well known in the field and including also for example ascorbyl palmitate and stearate.
- any dosage unit should not exceed that appropriate to the rate and manner of administration to be employed but on the other hand should also desirably be adequate to allow the desired rate of administration to be achieved by a small number of doses.
- the rate of administration will moreover depend on the precise pharmacological action desired.
- composition may also be in the form of whips, emulsions, suspensions, pessaries, suppositories, transdermal devices or any other appropriate forms.
- compositions and their administration for the purposes discussed herein.
Abstract
Description
- This invention relates to fatty acid treatments, and in particular to enhancing absorption of calcium from the gut,
-
- The above pathways are not normally reversible nor, in man, are n-3 and n-6 series acids interconvertible.
- The acids, which in nature are of the all-cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. delta-9,12-octadecadienoic acid or delta-4,7,10,13,16,19 docosahexaenoic acid, but numerical designations such as, correspondingly, 18:2 n-6 or 22:6 n-3 are convenient. Initials, for example, EPA for the 20:5 n-3 acid (eicosapentaenoic acid) or DHA for the 22:6 n-3 acid (docosahexaenoic acid), are also used but do not serve when n-3 and n-6 acids of the same chain length and degree of unsaturation exist as for example with the 22:5 acids. Trivial names in more or less common use in the n-6 series are as shown. Of the n-3 series only 18:3 n-3 has a commonly used trivial name, alpha-linolenic acid, though the name stearidonic acid is coming into use for the 18:4 n-3 acid and the names eicosapentaenoic acid and docosahexanenoic acid as such are also used. The alpha isomer of linolenic acid was characterised earlier than gamma-linolenic acid and reference in the literature simply to linolenic acid, especially in the earlier literature, is to the alpha-acid.
- Efficient absorption of calcium in humans and animals is significant for at least two reasons:
- 1. Low calcium absorption coupled with normal or excessive urine calcium excretion can lead to a negative calcium balance.
- 2. Calcium is required for normal bone strength, and inadequate gut calcium absorption can contribute to weakening of the bones and the development of osteoporosis, a major medical problem.
- It is known that lipid-calcium interactions are important in human nutrition. Laval-Jeantet et al disclose the stimulating effect of linoleic and alpha-linolenic acids on calcium absorption (Pathologie Biologie, vol. 24(3), 1976, pages 213-225). EP-0261814 discloses that the conversion of gammalinolenic acid to dihomogammalinolenic acid is inhibited by low calcium levels. The document teaches the co-administration of both calcium and these fatty acids to ensure that lack of either is not a limiting factor and proposes that this treatment may be of benefit in bone disorders involving calcium loss from the bones.
- We have previously discovered a new and safe way of reducing calcium excretion by the administration of gamma-linolenic acid (GLA), or GLA in combination with eicosapentaenoic acid (EPA), the subject of EP-A1-0,517,425. As discussed above, GLA is the first metabolite of linoleic acid, the major essential fatty acid in the diet. Linoleic acid is converted to GLA by the enzyme delta-6-desaturase. However, this step is slow and rate limiting even in the normal body and as a result there are advantages in the administration of GLA directly.
- Studies conducted in animals and in man showed that the optimal effect on reducing urine calcium excretion was achieved using a combination of GLA and EPA, although both fatty acids individually also elicited a response.
- Because of this, a further human clinical study was conducted in 30 recurrent, hypercalcuric stone formers. On entry into the trial all patients were taken off any previous treatment and stabilised on a standard calcium diet (800 mg calcium per day) which was maintained for the study period. After 14 days on the standard calcium diet, patients were allocated to one of 3 groups and given the following treatment for 12 weeks.
- Group 1
- 6g cold water marine fish oil (FO) per day (300 mg EPA);
- Group 2
- 6g evening primrose oil (EPO) per day (540 mg GLA);
- Group 3
- 6g of an 80:20 combination of EPO and FO (475 mg GLA, 238 mg EPA).
- At the end of the 14 day stabilisation period a baseline Ca45 absorption test was conducted and this was repeated after 12 weeks of treatment as above. The Ca45 absorption test results are summarised below:-
Treatment Baseline 12 weeks FO 0.36 ± 0.04 0.44 ± 0.06 EPO 0.38 ± 0.03 0.55 ± 0.07 EPO/FO 0.43 ± 0.07 0.68 ± 0.11 - There was a significant increase in fractional Ca45 absorption in both the EPO and EPO/FO treated patients although the latter were higher.
- Based on the above, the invention in one aspect lies in the use of GLA and/or its immediate and rapidly produced metabolite dihomogammalinolenic acid (DGLA), in the preparation of a medicament for, or in a method of, securing increase of gut calcium absorption. Because linoleic acid (LA) is a precursor of GLA it has some effect though its conversion is slow. The invention therefore includes the use of linoleic acid, and as noted below has particular reference to calcium deficiency disease.
- Alternatively, the invention may be regarded as lying in a method of increasing the systemic calcium pool by stimulating both an increased absorption of and a reduction of urinary excretion of calcium, wherein an effective daily amount of GLA or DGLA, or LA, is administered in any convenient form to animals or humans particularly those suffering from or at risk of calcium deficiency disease. The invention further includes the use of GLA, DGLA or LA in the preparation of a medicament for such a method.
- Equally in the use of GLA and/or DGLA in preparation of medicaments or in treatment as above, the invention may be regarded simply as the treatment or prevention condition defining disease in either animals or humans.
- As noted, GLA in the body is very rapidly converted to dihomo-gamma-linolenic acid (DGLA); DGLA therefore has a very similar effect to GLA.
- As discussed further below GLA or DGLA may be used in any appropriate form, including but not limited to triglyceride, diglyceride, monoglyceride, free fatty acid, any appropriate ester, any appropriate salt including the lithium, sodium, potassium, calcium, zinc, magnesium or other salt, phospholipid, amide or any other pharmacologically acceptable form.
- The preferred dose range is 0.01 to 1,000 mg/kg/day, more preferably 0.5 to 50 mg/kg/day, very preferably 2 to 30 mg/kg/day of GLA or DGLA, and medicaments are readily prepared in dosage unit form to administer such amounts (related to a 70 kg human adult).
- The GLA or DGLA may be used with any essential fatty acids of the n-6 or n-3 series, including, for example, arachidonic acid, alpha-linolenic acid, eicosapentaenoic acid or docosahexaenoic acid, in like doses. In particular, in view of results on human gut calcium absorption, GLA in combination with EPA and/or its metabolite DHA is desirable, producing particularly advantageous effects.
- Oral, parenteral (sub-cutaneous, intramuscular, intravenous or by any other appropriate route), enteral, topical in the form of appropriate GLA-containing ointments, creams, lotions, patches, etc. vaginal or rectal are among suitable routes of administration.
- As indicated above, the acids may be used as such or as pharmaceutically acceptable and physiologically equivalent derivatives as, for example, detailed herein for GLA and DGLA, and reference to any of the acids is to be taken as including reference to the acids when in the form of such derivatives. Equivalence is demonstrated by entry into the pathway quoted herein, as evidenced by effects corresponding to those of the acids themselves or their natural glyceride esters. Thus, indirect identification of useful derivatives is by their having the valuable effect in the body of the acid itself, but conversion can be shown directly by gas chromatographic analysis of concentrations in blood, body fat, or other tissue by standard techniques, for example those of Pelick et al, page 23, "Analysis of Lipids and Lipoproteins" Ed Perkins, American Oil Chemists Society, Champaign, Illinois, U.S.A.
- In outline the method is suitably that plasma samples (1 ml) are extracted with chloroform:methanol (2:1). The extract is filtered through sodium sulphate, evaporated to dryness, and taken up in 0.5 ml chloroform:methanol. The lipid fractions are separated by thin layer chromatography or silica gel plates. The phospholipid fraction, taken to reflect essential fatty acid contents most sensitively, is methylated using boron trifluoride-methanol. The resulting methyl esters of the fatty acids are separated and measured using a Hewlett-Packard 5880 gas chromatograph with a six foot column packed with 10% Silar on Chromosorb WAW 106/230. The carrier gas is helium (30 ml/min). Oven temperature is programmed to rise from 164°C to 190°C at 2°C/min. Detector temperature is 220°C and injector temperature 200°C. Retention times and peak areas are automatically computed by Hewlett-Packard Level 4 integrator. Peaks are identified by comparison with standard fatty acid methyl esters.
- The invention is chiefly described in terms of methods of treatment and in the use of GLA or DGLA in the preparation of pharmaceutical compositions, but it will be understood that the gamma-linolenic and other EFAs, being in the nature of dietary supplements, can be incorporated in a dietary margarine or other foodstuff and such are to be understood as within the term pharmaceutical composition or medicament herein (including the claims) when for the purposes set out.
- If desired, pharmaceutical compositions may be produced for use in the invention by associating the natural or synthetic acids, as such or as derivatives, with an acceptable pharmaceutical vehicle. It is, however, at present convenient to provide at least GLA in the form of an available oil having a high GLA content, hence reference to "oils" herein.
- One source of oils currently available is the seed of evening primrose species such as Oenothera biennis L. and Oenothera lamarckiana, the oil extract therefrom containing about 8% GLA and about 72% linoleic acid in the form of their glycerides, together with other glycerides (percentages based on total fatty acids). Other sources of GLA are borage species such as Borago officinalis which provide a richer source than Oenothera oil. Oils from the seeds of members of the Ribes family are also often rich in GLA. Recent studies on fungi which can be cultivated by fermentation promise a fungal oil source. Some algae also produce GLA and may be harvested or cultured. Synthesis is also possible.
- The oil is extracted from the seed by one of the conventional methods of extraction such as cold pressure, screw pressure after partially cooking the seed, or solvent extraction.
- Fractionation of a typical sample of evening primrose oil as used in the work reported herein in the form of methyl esters shows the relative proportions:
Palmitate 6.15 Stearate 1.6 Oleate 10.15 Linoleate 72.6 Gamma-linolenate 8.9 - The seed oil extracts referred to above can be used as such or can, for example, if desired, be fractionated to yield an oily composition containing the triglycerides of gamma-linolenic and linoleic acids as the main fatty acid components, the gamma-linolenic acid content being, if desired, a major proportion. Seed oil extracts appear to have a stabilising effect upon DGLA if present.
- DGLA can be prepared by chemical synthesis or by fungal or algal fermentation. For the higher n-6 acids, natural sources of 22:4 and 22:5 n-6 acids include adrenal glands (22:5) and kidneys (22:4) obtained from slaughter houses, which also give arachidonic acid (AA) sources.
- Tile n-3 acids have long been available from marine oils, particularly the 20:5 n-3 (EPA) and 22:6 n-3 (DHA) acids, and more recently from microbial and algal fermentation. They can be isolated from these sources by, for example, saponification under mild non-oxidising conditions followed by preparative gas liquid chromatography. Synthesis is difficult but not impossible and provides another source.
- As mentioned briefly above, the compositions are conveniently in a form suitable for oral, topical, parenteral or other route of administration in a suitable pharmaceutical vehicle, well known generally for any particular kind of preparation. Thus, for example, tablets, capsules, ingestible liquid or powder preparations can be prepared as required, and topical preparations also when the gamma-linolenic acid or other acids are absorbed through the skin. Injectable solutions of hydrolysed Oenothera or other oil may be prepared using albumin to solubilise the free acid. Emulsions and salts can also be administered by infusion or injection.
- Advantageously, a preservative is incorporated into the preparation. Alpha-tocopherol in a concentration of about 0.1% by weight has been found suitable for the purpose and is one of a number of possible stabilisers well known in the field and including also for example ascorbyl palmitate and stearate.
- It will be understood that the absolute quantity of active materials present in any dosage unit should not exceed that appropriate to the rate and manner of administration to be employed but on the other hand should also desirably be adequate to allow the desired rate of administration to be achieved by a small number of doses. The rate of administration will moreover depend on the precise pharmacological action desired.
- The composition may also be in the form of whips, emulsions, suspensions, pessaries, suppositories, transdermal devices or any other appropriate forms.
- The following are examples of compositions and their administration for the purposes discussed herein.
- 1. Administration of 100 mg to 2,000 mg of GLA per day in the form of soft or hard gelatin capsules or tablets providing:
- a. 40 to 80 mg per capsule of GLA in the form of evening primrose oil.
- b. 50-150 mg per capsule of GLA in the form of borage, blackcurrant, fungal or other appropriate oil.
- c. 100-150 mg GLA per capsule in the form of triglyceride GLA, or any appropriate salt of GLA, such as the lithium or calcium or magnesium or zinc or potassium salts.
- 2. Administration of DGLA in a dose of 100 mg to 2,000 mg per day in the forms of 1c above.
- 3. Administration of GLA or DGLA in association with EPA, with or without DHA, for example as 40 to 80 mg GLA per capsule in the form of evening primrose oil together with 10 mg to 100 mg per capsule of EPA in the form of cold water marine fish oil.
- 4. Administration of GLA or DGLA in the form of a soluble powder or effervescent granule formed from any appropriate salt of GLA as in 1c above and excipients such as citric acid monohydrate, sodium bicarbonate or other dibasic acids such as tartaric or maleic acid plus sweeteners such as sucrose or sorbitol and flavourings.
- 5. Administration of GLA or DGLA in the form of liquid evening primrose, borage or other appropriate oil as the oil itself or as a whip or emulsion prepared with appropriate flavours and stabilisers.
- 6. Administration of GLA or DGLA in any appropriate chemical form, microencapsulated using starch, gelatin, gum arabic or other appropriate formulation.
- 7. Administration of GLA in the form of pessaries, suppositories, skin patches or any other appropriate route.
- 8. Calcium-GLA tablets or soft or hard gelatin capsules containing 500 mg of calcium-GLA salt to be taken 1-5 times/day.
Claims (7)
- Use of gamma-linolenic acid (GLA) or dihomogammalinolenic acid (DGLA) as such or in salt or other pharmacologically acceptable form, optionally in association with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or other n-6 or n-3 series essential fatty acid, additional to the GLA or DGLA, as such or in salt or other pharmacologically acceptable form, in the preparation of a medicament for increasing gut calcium absorption for treating calcium deficiency diseases other than osteoporosis.
- Use of GLA or DGLA as such or in salt or other pharmacologically acceptable form, optionally in association with EPA, DHA or other n-6 or n-3 series essential fatty acid, additional to the GLA or DGLA, as such or in salt or other pharmacologically acceptable form, in the preparation of a medicament for increasing the systemic calcium pool by stimulating both an increased absorption of and a reduction of urinary excretion of calcium for treating calcium deficiency diseases other than osteoporosis.
- A use according to claims 1 or 2 wherein one or more of the essential fatty acids is/are present in the medicament as calcium salt(s).
- A use according to claims 1, 2 or 3 wherein the medicament comprises a dose range of the or each essential fatty acid suited to administration of from 0.01 to 1,000 mg/kg/day.
- A use according to claims 1, 2 or 3 wherein the medicament comprises a dose range of the or each essential fatty acid suited to administration of from 0.5 to 50 mg/kg/day.
- A use according to claims 1, 2 or 3 wherein the medicament comprises a dose range of the or each essential fatty acid suited to administration of from 2 to 30 mg/kg/day.
- A use according to any preceding claim, wherein the medicament is presented in unit dosage form.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9217780 | 1992-08-21 | ||
GB929217780A GB9217780D0 (en) | 1992-08-21 | 1992-08-21 | Fatty acid treatment |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0585026A1 EP0585026A1 (en) | 1994-03-02 |
EP0585026B1 true EP0585026B1 (en) | 1997-11-05 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP93306444A Expired - Lifetime EP0585026B1 (en) | 1992-08-21 | 1993-08-16 | Use of fatty acids for increasing gut calcium absorption |
Country Status (21)
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US (1) | US5618558A (en) |
EP (1) | EP0585026B1 (en) |
JP (1) | JPH06157303A (en) |
KR (1) | KR940003553A (en) |
CN (1) | CN1049334C (en) |
AT (1) | ATE159856T1 (en) |
AU (1) | AU666747B2 (en) |
CA (1) | CA2104567A1 (en) |
DE (1) | DE69315020T2 (en) |
DK (1) | DK0585026T3 (en) |
ES (1) | ES2110060T3 (en) |
GB (1) | GB9217780D0 (en) |
GR (1) | GR3025898T3 (en) |
HK (1) | HK1000997A1 (en) |
MY (1) | MY109928A (en) |
NO (1) | NO306655B1 (en) |
NZ (1) | NZ248422A (en) |
RU (1) | RU2122409C1 (en) |
SG (1) | SG80536A1 (en) |
TW (1) | TW323230B (en) |
ZA (1) | ZA935976B (en) |
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ES2877810T3 (en) * | 2016-06-01 | 2021-11-17 | Nestle Sa | DGLA in the prophylaxis of allergic diseases |
WO2018213663A1 (en) | 2017-05-19 | 2018-11-22 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides in a subject having reduced kidney function |
US11058661B2 (en) | 2018-03-02 | 2021-07-13 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides in a subject on concomitant statin therapy and having hsCRP levels of at least about 2 mg/L |
KR102296068B1 (en) | 2018-09-24 | 2021-09-02 | 애머린 파마슈티칼스 아일랜드 리미티드 | Methods of Reducing the Risk of a Cardiovascular Event in a Subject |
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Publication number | Priority date | Publication date | Assignee | Title |
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GB1417119A (en) * | 1972-11-30 | 1975-12-10 | Thiele G H | Process for treating bones |
GB8621816D0 (en) * | 1986-09-10 | 1986-10-15 | Efamol Ltd | Therapeutic composition |
JPH0625057B2 (en) * | 1987-12-14 | 1994-04-06 | 日本油脂株式会社 | Bone formation promoter |
GB9112052D0 (en) * | 1991-06-05 | 1991-07-24 | Efamol Holdings | Fatty acid treatment |
-
1992
- 1992-08-21 GB GB929217780A patent/GB9217780D0/en active Pending
-
1993
- 1993-08-16 EP EP93306444A patent/EP0585026B1/en not_active Expired - Lifetime
- 1993-08-16 DK DK93306444.6T patent/DK0585026T3/en active
- 1993-08-16 JP JP5202396A patent/JPH06157303A/en active Pending
- 1993-08-16 AU AU44666/93A patent/AU666747B2/en not_active Ceased
- 1993-08-16 ZA ZA935976A patent/ZA935976B/en unknown
- 1993-08-16 ES ES93306444T patent/ES2110060T3/en not_active Expired - Lifetime
- 1993-08-16 US US08/106,989 patent/US5618558A/en not_active Expired - Fee Related
- 1993-08-16 SG SG9605801A patent/SG80536A1/en unknown
- 1993-08-16 DE DE69315020T patent/DE69315020T2/en not_active Expired - Fee Related
- 1993-08-16 AT AT93306444T patent/ATE159856T1/en not_active IP Right Cessation
- 1993-08-17 NZ NZ248422A patent/NZ248422A/en unknown
- 1993-08-20 CA CA002104567A patent/CA2104567A1/en not_active Abandoned
- 1993-08-20 RU RU93049153A patent/RU2122409C1/en active
- 1993-08-20 KR KR1019930016204A patent/KR940003553A/en not_active Application Discontinuation
- 1993-08-20 NO NO932983A patent/NO306655B1/en not_active IP Right Cessation
- 1993-08-21 MY MYPI93001672A patent/MY109928A/en unknown
- 1993-08-21 CN CN93118320A patent/CN1049334C/en not_active Expired - Fee Related
- 1993-08-23 TW TW082106797A patent/TW323230B/zh active
-
1997
- 1997-12-29 HK HK97102670A patent/HK1000997A1/en not_active IP Right Cessation
-
1998
- 1998-01-14 GR GR980400071T patent/GR3025898T3/en unknown
Also Published As
Publication number | Publication date |
---|---|
ATE159856T1 (en) | 1997-11-15 |
ES2110060T3 (en) | 1998-02-01 |
US5618558A (en) | 1997-04-08 |
CN1091285A (en) | 1994-08-31 |
DE69315020T2 (en) | 1998-04-16 |
JPH06157303A (en) | 1994-06-03 |
NO306655B1 (en) | 1999-12-06 |
RU2122409C1 (en) | 1998-11-27 |
KR940003553A (en) | 1994-03-12 |
CA2104567A1 (en) | 1994-02-22 |
ZA935976B (en) | 1994-03-14 |
NO932983D0 (en) | 1993-08-20 |
NO932983L (en) | 1994-02-22 |
AU666747B2 (en) | 1996-02-22 |
TW323230B (en) | 1997-12-21 |
GR3025898T3 (en) | 1998-04-30 |
EP0585026A1 (en) | 1994-03-02 |
SG80536A1 (en) | 2001-05-22 |
HK1000997A1 (en) | 1998-05-15 |
GB9217780D0 (en) | 1992-10-07 |
NZ248422A (en) | 1997-06-24 |
MY109928A (en) | 1997-09-30 |
DE69315020D1 (en) | 1997-12-11 |
DK0585026T3 (en) | 1998-06-02 |
AU4466693A (en) | 1994-02-24 |
CN1049334C (en) | 2000-02-16 |
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